The long term objective of the present proposal is to help clarify the question of how opiate analgesics relieve pain. There are several loci in brain where opiate receptors are located and where electrical and/or chemical (opiate) activation produces analgesia. These structures connect to pain pathways along multiple routes. A systemic injection of opiates must activate many of these substrates in a complex dynamic manner. The approach proposed is to examine effects of single and conjoint activation of two opiate substrates in rat, the midbrain periacqueductal gray (PAG) and the nucleus reticularis paragigantocellularis (PGC), on recorded responses of single neurons in nucleus raphe magnus (NRM) and in trigeminal nucleus caudalis (TNC). Met-Enkephalin will be microcannulated into PAG and PGC singly and together and it will be determined whether or not (and if so, how) these two opiate substrates can influence the same cell in NRM, an opiate substrate itself; and in TNC, the origin of a pain pathway. Dose-response studies of the effects of morphine in PGC will also be done. Time permitting, effects of PGC lesions on PAG morphine-evoked modification of NRM and TNC unit activity will also be investigated.